Skeletal Morbidity Research Articles

Hormone replacement therapy after treatment for a gynaecological malignancy.

Provision of hormone replacement therapy (HRT) to women following a diagnosis of a gynaecological malignancy is a complex and controversial area associated with a lack of published guidance. As the average age of women affected by gynaecological cancer decreases and survival following provision of effective therapies increases, clinicians face new considerations for longer-term health concerns of patients. Additionally, there is a growing understanding of the influence of tumour biology upon response to cytotoxic therapies and it is essential that we use this knowledge to guide provision of HRT. Available evidence for ovarian, vulval, cervical, and endometrial cancers demonstrates no excess risk of recurrence in patients taking HRT with the exception of some subtypes of cancer (uterine sarcomas, granulosa cell, and low-grade serous ovarian cancer). Evidence for the incidence of hormone receptor status is suggestive that HRT may be ill-advised in an additional proportion of patients and we recommend characterization of all tumours in patients who may require HRT. The risk and benefits of HRT should be evaluated for all women who undergo a premature menopause as a result of gynaecological malignancy to reduce menopausal symptoms and protect against cardiovascular and skeletal morbidity. There is no evidence to suggest a higher rate of disease recurrence in women using HRT in comparison to nonusers in the majority of gynaecological malignancies. Routine histological testing of tumours for hormone receptor status is an achievable goal and may help to stratify patients further into low and high-risk groups for hormone therapy.

Bone Metastasis: Molecular Mechanisms Implicated in Tumour Cell Dormancy in Breast and Prostate Cancer

Metastasis to the bone is most frequently observed in advanced cases of breast and prostate cancer. The latent development of overt metastatic lesions is associated with debilitating skeletal morbidity and eventual patient mortality. Secondary tumours in bone are derived from disseminated tumour cells (DTCs) that enter into a state of cellular dormancy. The dormant state confers resistance to conventional chemotherapeutic agents and prevents elimination of DTCs from the bone using current drug therapies. Expansion of our presently limited understanding of the molecular mechanisms underpinning disseminated breast and prostate tumour cell dormancy is critical to the future development of novel drug therapies aimed at the removal of DTCs, and thereby, the prevention of bone metastasis. This review provides an overview of the main putative molecular mechanisms underlying cellular dormancy in breast and prostate cancer bone metastasis reported from multiple experimental in vitro and in vivo models.

Skeletal morbidities in the prostate cancer (PC) patient.

e16106 Background: Individuals with PC are at risk for skeletal complications and functional impairments secondary to metastatic disease and treatments. Underappreciated is the impact of age relate...

Targeting bone metastases in prostate cancer: improving clinical outcome

Bone metastases develop in most patients with metastatic castration-resistant prostate cancer (mCRPC). They affect the structural integrity of bone, manifesting as pain and skeletal-related events (SREs), and are the primary cause of patient disability, reduced quality of life (QOL) and death. Understanding the pathophysiology of bone metastases resulted in the development of agents that improve clinical outcome, suggesting that managing both the systemic disease and associated bone events is important. Historically, the treatment of CRPC bone metastases with early radiopharmaceuticals and external beam radiation therapy was largely supportive; however, now, zoledronic acid and denosumab are integral to the therapeutic strategy for mCRPC. These agents substantially reduce skeletal morbidity and improve patient QOL. Radium-223 dichloride is the first bone-targeting agent to show improved survival and reduced pain and symptomatic skeletal events in patients with mCRPC without visceral disease. Five other systemic agents are currently approved for use in mCRPC based on their ability to improve survival. These include the cytotoxic drugs docetaxel and cabazitaxel, the hormone-based therapies, abiraterone and enzalutamide, and the immunotherapeutic vaccine sipuleucel-T. Abiraterone and enzalutamide are able to reduce SREs and improve survival in this setting. Novel agents targeting tumour and bone cells are under clinical development.

Traitements inhibiteurs de la résorption osseuse en situation métastatique : bilan actuel et perspectives

The current main use of inhibitors of bone resorption, bisphosphonates and denosumab, is the prevention of the complications of bone metastases. Monthly infusions of zoledronic acid, the most potent bisphosphonate, decrease the complication rate of tumor-induced osteolysis by about 40%. Recent controlled double-blind phase III trials have demonstrated the superiority of denosumab against zoledronic acid to decrease skeletal morbidity in patients with bone metastases from breast or prostate cancer, and its noninferiority in a third trial including patients with other solid tumors or myeloma. The overall toxicity was similar between both compounds. It is recommended to start an inhibitor of bone resorption as soon as bone metastases are diagnosed, at least in patients with breast cancer. However, the optimal duration of therapy is unknown and we lack validated criteria to better individualize therapy and to define the place of intermittent treatments or of larger intervals between infusions. Lastly, recent studies indicate that zoledronic acid, but also clodronate, are able to reduce the risk of bone metastases and to prolong survival, at least in postmenopausal patients with breast cancer after surgery. This use of inhibitors of bone resorption in the adjuvant setting is not admitted yet although clinical practice is likely to change in the near future.

Defective skeletal mineralization in pediatric CKD.

Although traditional diagnosis and treatment of renal osteodystrophy focused on changes in bone turnover, current data demonstrate that abnormalities in skeletal mineralization are also prevalent in pediatric chronic kidney disease (CKD) and likely contribute to skeletal morbidities that continue to plague this population. It is now clear that alterations in osteocyte biology, manifested by changes in osteocytic protein expression, occur in early CKD before abnormalities in traditional measures of mineral metabolism are apparent and may contribute to defective skeletal mineralization. Current treatment paradigms advocate the use of 1,25(OH)2vitamin D for the control of secondary hyperparathyroidism; however, these agents fail to correct defective skeletal mineralization and may exacerbate already altered osteocyte biology. Further studies are critically needed to identify the initial trigger for abnormalities of skeletal mineralization as well as the potential effects that current therapeutic options may have on osteocyte biology and bone mineralization.

Osteonecrosis of the Jaw After Bisphosphonates Treatment in Patients with Multiple Myeloma.

Background:Bone lytic lesion in Multiple myeloma are the most commonly presented symptoms which require treatment with bisphosphonates (BPs). BPs are providing supportive care, reducing the rate of skeletal morbidity but evidently not abolishing it, the criteria for stopping their administration have to be different from those used for classic antineoplastic drugs, and they should not be stopped when metastatic bone disease is progressing. Osteonecrosis of the jaw (ONJ) has been associated recently with the use of BPs.Aim:The aim of these study is to evaluate the incidence of ONJ in patients with MM treated with mixed biphosphonates.Patients and methods:We analyzed total 296 myeloma patients (150 male and 146 female). Mostly effected age group with 58,1% is age more than 60 years up to 88 years, diagnosed in our institution in the period 2005-2015. We used intravenous or oral forms of biphosphonates such as pamidronate, ibandronate, clodronate and zolendronic acid. The patients were evaluated for ONJ.Results:The incidence of ONJ in our group of patients treated with Bps was 4,6% from our group of 260 patients 87,8% received BPs therapy and patients which haven’t received BPs 12,2%. From this group, 95,4% (248) didn’t show ONJ, and 4,6% (12) showed ONJ. The period of this treatment with BPs is an important risk factor for development of ONJ, average duration of BPs therapy in patients which show adverse effects is 26.8±13.7 months, from the total number of 12 patients that developed ONJ adverse effects, we have 8 patients which received treatment with Zolendronic acid and the remaining 4 patients which were treated with other BPs combinations without Zolendronic acid.Conclusions:All patients treated for MM must continue with the therapy with Zolendronic acid and Pamidronate, each patient must be individually treated according to his response of the treatment (dose, frequency and duration of therapy).

No association between BMD and prevalent vertebral fractures in liver transplant recipients at time of screening before transplantation.

Osteoporosis and fractures are prevalent after orthotopic liver transplantation (OLT), but data on these skeletal complications are scarce in patients with end-stage liver disease awaiting liver transplantation. To evaluate the prevalence of vertebral fractures (VFs) in OLT recipients at the time of screening for transplantation and to establish the association between bone mineral density (BMD) and these fractures before transplantation. We conducted a retrospective study of consecutive OLT recipients at the Leiden University Medical Centre between 2000 and 2011 at the time of screening for transplantation. Clinical, laboratory, and BMD data were extracted from electronic hospital records. Conventional spinal radiographs were assessed for VF by two independent observers using Genant's semiquantitative method. In total, 162 of the 223 OLT recipients (median age, 51 y; 75% men) who had available BMD and spinal radiographs but who were not receiving bone-modifying treatment at screening for OLT were included in the study. Association between BMD and VF before transplantation. Osteoporosis and osteopenia were prevalent at the lumbar spine in 19 and 38% of subjects, respectively, and in 10 and 42 % at the femoral neck. VFs, mostly grade 1, were prevalent in 56% of the subjects. There was no association between BMD and prevalent VF before transplantation. VFs were prevalent in liver transplant recipients at the time of screening for transplantation, but there was no association between BMD and prevalent fractures. Spinal radiographs should be routinely performed as part of screening protocols before liver transplantation to enable identification of VF and allow timely intervention to potentially decrease or prevent skeletal morbidity after transplantation.

Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: Results of the OPTIMIZE-2 trial.

LBA9500^ Background: Zoledronic acid (ZOL, 4 mg) every (q) 4 wk reduces the risk of skeletal-related events (SREs) in patients (pts) with bone metastases from breast cancer (BC). The OPTIMIZE-2 trial examined whether ZOL q12 wk was non-inferior to ZOL q4 wk in pts who had previously received monthly IV bisphosphonate (BP) therapy for ~1 year or longer. Methods: This was a prospective, randomized, double-blind, multicenter trial in female pts with bone metastases from BC who previously received ≥9 doses of IV BP (ZOL or pamidronate) during the first 10-15 months of therapy. Pts were randomized (1:1) to receive ZOL 4 mg IV q4 wk or q12 wk (placebo between ZOL doses to maintain blind) for 1 year. The primary endpoint was the proportion of pts with ≥1 SRE on study (SRE rate). Primary analysis was non-inferiority (pre-defined margin of 10%) for the difference in SRE rates. Secondary endpoints included time to first SRE, skeletal morbidity rate (SMR), bone pain score, change in bone turnover markers, and safety. Results: 403 pts were randomized to ZOL q4 wk (n = 200) or q12 wk (n = 203). Median age was 59 years, and baseline characteristics were similar between arms. The SRE rate was 22% and 23.2% in the ZOL q4 and q12 wk arms, respectively. The difference in SRE rate between arms was 1.2% (95% CI, –7.5% to 9.8%; P = .724). The upper limit of this 95% CI (9.8%) is less than the predefined margin of 10%, which indicates non-inferiority of ZOL q12 wk vs q4 wk. Times to first on-study SRE (HR, 1.06; 95% CI, 0.70 to 1.60; P = .792) were similar in the ZOL q4 and q12 wk arms, and mean SMRs were also similar (0.46 vs 0.50, respectively; P = .854). Overall, changes from baseline in bone turnover markers, and the incidence of treatment-emergent adverse events (TEAEs), were similar in the 2 arms. Numerically more renal TEAEs were reported in the ZOL q4 wk vs q12 wk arm (9.6% vs 7.9%, respectively). Two cases (1.0%) of osteonecrosis of the jaw (ONJ) were reported in the q4 wk arm. Conclusions: Among pts who had received monthly IV BP therapy for 1 year or longer, the efficacy of continuing ZOL for an additional year at q12 wk was non-inferior to ZOL q4 wk. Fewer renal AEs and none of the ONJ events were observed in the ZOL q12 wk vs ZOL q4 wk arm. Clinical trial information: NCT00320710.

Managing bone metastases and reducing skeletal related events in prostate cancer.

Advanced-stage prostate cancer is associated with skeletal complications related to metastatic disease and its treatment. On the one hand, metastatic disease to bone is commonly associated with skeletal-related events (SREs); on the other hand, treatment with androgen-deprivation therapy (ADT) leads to loss in bone mineral density (BMD) and increased risk of fracture. Despite osteoblastic appearance on radiography, bone metastases from prostate cancer are associated with increased osteoblast and osteoclast activity providing the rationale for treatment with osteoclast-targeted agents. The bisphosphonate zoledronic acid and the monoclonal antibody denosumab reduce the incidence of SREs in metastatic castration-resistant prostate cancer (mCRPC). A number of agents prevent loss of BMD associated with ADT, but only denosumab is approved to reduce fractures in patients with non-metastatic prostate cancer. Another recently approved agent-radium-223-improves survival and delays SREs in mCRPC. The inhibitors of androgen receptor signalling, abiraterone and enzalutamide, improve survival in mCRPC and delay SREs, although the latter is likely related to control of disease rather than a direct effect on bone. Finally, the tyrosine kinase inhibitor cabozantinib shows promising activity in bone metastases from mCRPC. This Review addresses the skeletal morbidity associated with prostate cancer and the therapeutic options that exist to treat it.

G257(P) Vitamin D Status in Paediatric Oncology Patients at a DGH

AimsThis study was undertaken following observation of a number of fractures in the paediatric oncology population at a district general hospital (DGH), some, after minimal trauma. Research indicates that children...

Painful Boney Metastases

Up to 90% of patients with metastatic or advanced stage cancer will experience significant cancer-related pain. Approximately half or more of patients diagnosed with cancer may experience bone pain. It has been estimated that tumor metastases to the skeleton affects roughly 400,000 US citizens annually. Carcinoma from breast, lung, and prostate cancers account for approximately 80% of secondary metastatic bone disease. Bone metastases may cause devastating clinical complications associated with dramatic reductions in quality of life, mobility, and independence, as well as excruciating refractory pain. Associated complications from osseous metastases also present a substantial economic burden. Currently, there are still a significantly high number of patients suffering with unrelieved pain from osseous metastases. Treatments for painful osseous metastases may not only diminish pain but also may improve quality of life and independence/mobility, and reduce skeletal morbidity, potential pathologic fractures, spinal cord compression, and other "skeletal-related events." Treatment strategies for painful osseous metastases include the following: systemic analgesics, intrathecal analgesics, glucocorticoids, radiation (external beam radiation, radiopharmaceuticals), ablative techniques (radiofrequency ablation and cryoablation), bisphosphonates, chemotherapeutic agents, inhibitors of RANKL-RANK interaction (eg, denosumab), hormonal therapies, interventional techniques (eg, kyphoplasty), and surgical approaches. Although the mechanisms underlying the development of bone metastases remain incompletely understood, there appears to be important bi-directional interactions between the tumor and the bone microenvironment. A greater understanding of the pathophysiology of painful osseous metastases may lead to better and more selective targeted analgesic therapy. Additionally, potential future therapeutic approaches to painful osseous metastases may revolutionize approaches to analgesia for this condition, leading to optimal outcomes with maximal pain relief and minimal adverse effects.

Medical Treatment of Breast Cancer Bone Metastasis: From Bisphosphonates to Targeted Drugs

Breast cancer bone metastasis causing severe morbidity is commonly encountered in daily clinical practice. It causes pain, pathologic fractures, spinal cord and other nerve compression syndromes and life threatening hypercalcemia. Breast cancer metastasizes to bone through complicated steps in which numerous molecules play roles. Metastatic cells disrupt normal bone turnover and create a vicious cycle to which treatment efforts should be directed. Bisphosphonates have been used safely for more than two decades. As a group they delay time to first skeletal related event and reduce pain, but do not prevent development of bone metastasis in patients with no bone metastasis, and also do not prolong survival. The receptor activator for nuclear factor κB ligand inhibitor denosumab delays time to first skeletal related event and reduces the skeletal morbidity rate. Radionuclides are another treatment option for bone pain. New targeted therapies and radionuclides are still under investigation. In this review we will focus on mechanisms of bone metastasis and its medical treatment in breast cancer patients.

Denosumab for the prevention of symptomatic skeletal events in patients with castration-resistant advanced prostate cancer: A comparison with skeletal-related events.

35 Background: In a randomized controlled trial of men with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid (ZA) for reducing skeletal-related events (SRE, defined as pathological fracture, surgery or radiation to bone [including the use of radioisotopes], or spinal cord compression) (Fizazi, et al. Lancet 2011;377:813-822.). Recently, the composite endpoint of symptomatic skeletal event (SSE, defined as symptomatic fracture, surgery or radiation to bone, or spinal cord compression) was introduced as an alternative term/clinical trial endpoint to describe skeletal morbidity. Methods: Men with CRPC, ≥ 1 bone metastasis, and no prior IV bisphosphonate use received either SC denosumab 120 mg or IV ZA 4 mg (adjusted for creatinine clearance) in a blinded fashion every 4 weeks. Oral calcium and vitamin D supplements were recommended. SSEs included pathologic fractures considered symptomatic by the investigator, spinal cord compression and surgery and radiation to bone. Results: As previously reported, fewer men who received denosumab than ZA had confirmed first SREs, and experienced multiple SREs (Table). Similarly, fewer patients in the denosumab group than the ZA group had confirmed first SSE and multiple SSEs. The median (95% CI) estimate of time to first SSE (superiority analysis) for denosumab was not reached (28.8 mo, not estimable), and for ZA it was 24.2 (20.7, 30.2) mo (HR = 0.78 (0.66, 0.93) P = 0.01). Conclusions: Denosumab reduced the risk of skeletal events in men with CRPC regardless of endpoint definition as SRE or SSE. The risk of developing SSEs was reduced by up to 22% when comparing denosumab with ZA. Clinical trial information: NCT00321620. [Table: see text]

Bone targeted therapies for the prevention of skeletal morbidity in men with prostate cancer

Men with prostate cancer suffer substantially from bone-related complications. Androgen deprivation therapy itself is a cause of loss of bone mineral density and is associated with an increased incidence of osteoporotic fractures. In advanced disease, bone is by far the most common site of metastasis. Complications of bone metastases prominently include pain and the potential for skeletal events such as spinal cord compression and pathologic fractures. Elevated osteoclast activity is an important aspect of the pathophysiology of both treatment-related osteoporosis and skeletal complications due to metastases. The osteoclast is therefore a therapeutic target. Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor-κ-B ligand that was designed to potently inhibit osteoclast activity and is the central focus of this review. Bisphosphonates, radiopharmaceuticals and systemically-active hormonal agents such as abiraterone acetate and enzalutamide have each been shown to improve skeletal morbidity in specific clinical situations. Denosumab is the only agent that has been shown to prevent osteoporotic fractures in men receiving androgen deprivation therapy and at elevated risk for fracture. It has also demonstrated superiority to the potent bisphosphonate zoledronic acid for the prevention of skeletal-related events in men with castration-resistant prostate cancer metastatic to bone. Efficacy and toxicity data will be discussed.

Pathological fractures in paediatric patients with inflammatory bowel disease

Paediatric inflammatory bowel disease (IBD), especially Crohn's disease (CD), is commonly associated with poor skeletal health, related to the direct effects of chronic inflammation, prolonged use of glucocorticoid (GC), poor nutrition, delayed puberty and low muscle mass. Low bone mineral density is commonly reported, although the prevalence of long bone fractures may not be increased in these patients. Emerging evidence however suggests that there may be an increased risk of vertebral fractures (VFs) in this group. VFs presenting at diagnosis of paediatric CD, prior to any GC exposure, have been reported, highlighting the deleterious effect of inflammation on skeletal health. This paper reviews the published literature on pathophysiology of skeletal morbidity and fractures in paediatric IBD, illustrated with a new case report of multiple VFs in a prepubertal girl with CD, soon after diagnosis, who received minimal amounts of oral GC. Optimising control of disease, addressing vitamin D deficiency, encouraging physical activity and ensuring normal growth and pubertal progression are paramount to management of bone health in these patients. Despite the lack of evidence, there may be a place for bisphosphonate treatment, especially in the presence of symptomatic pathological fractures, but this requires close monitoring by clinicians with expertise in paediatric bone health. Chronic inflammation mediated by pro-inflammatory cytokines may have adverse effects on skeletal health in paediatric patients with IBD. The risk of vertebral fractures may be increased, even without exposure to glucocorticoid. Clinical monitoring of these patients requires careful attention to the various factors that impact on bone health.

Denosumab and Giant Cell Tumour of Bone—A Review and Future Management Considerations

Giant cell tumour of bone (gctb) is one type of giant-cell-rich bone lesion characterized by the presence of numerous multinucleated osteoclast-type giant cells. Giant cells are known to express rankl (receptor activator of nuclear factor κB ligand) and are responsible for the aggressive osteolytic nature of the tumour. No available treatment option is definitively effective in curing this disease, especially in surgically unsalvageable cases. In recent years, several studies of denosumab in patients with advanced or unresectable gctb have shown objective changes in tumour composition, reduced bony destruction, and clinical benefit. Denosumab is a fully human monoclonal antibody that targets and binds with high affinity and specificity to rankl. Several large phase iii studies have shown that denosumab is more effective than bisphosphonates in reducing skeletal morbidity arising from a wide range of tumours and that it can delay bone metastasis. The relevant articles are reviewed here. The controversies related to the future use of denosumab in the treatment of gctb are discussed.

Managing hypercalcaemia and hypocalcaemia in cancer patients

Hypercalcaemia is commonly associated with cancer which is usually advanced and portends a poor prognosis. Hypocalcaemia is more often seen as a complication of therapy aimed at reducing skeletal morbidity rather than an effect of the cancer itself. We present an overview of calcium disorders in malignant disease. A significant proportion of patients who have a cancer and become hypercalcaemic have an alternative cause for their hypercalcaemia.Evidence for the use of loop diuretics is lacking, and such agents should not be routinely used unless significant volume overload occurs during rehydration. Bisphosphonates are generally established as first-line therapy after volume expansion with saline. As knowledge of bone biology increases, there is interest in the use of the mAb denosumab, for the management refractory hypercalcaemia. Knowledge of the vitamin D status, and supplementation of vitamin D, may reduce the risk of hypocalcaemia when potent antiresorptive medications are being used. Calcium disorders can be predicted in many tumour types and with antiresorptive therapy. A logical approach to prevention and management of these imbalances should be incorporated into cancer patient care.

Prostate cancer metastases alter bone mineral and matrix composition independent of effects on bone architecture in mice — A quantitative study using microCT and Raman spectroscopy

Prostate cancer is the most common primary tumor and the second leading cause of cancer-related deaths in men in the United States. Prostate cancer bone metastases are characterized by abnormal bone remodeling processes and result in a variety of skeletal morbidities. Prevention of skeletal complications is a crucial element in prostate cancer management. This study investigated prostate cancer-induced alterations in the molecular composition and morphological structure of metastasis-bearing bones in a mouse model of prostate cancer using Raman spectroscopy and micro-computed tomography (microCT). LNCaP C4-2B prostate cancer cells were injected into the right tibiae of 5-week old male SCID mice. Upon sacrifice at 8weeks post tumor inoculation, two out of the ten tumor-bearing tibiae showed only osteoblastic lesions in the radiographs, 4 osteolytic lesions only and 4 mixed with osteoblastic and osteolytic lesions. Carbonate substitution was significantly increased while there was a marked reduction in the level of collagen mineralization, mineral crystallinity, and carbonate:matrix ratio in the cortex of the intact tumor-bearing tibiae compared to contralateral controls. MicroCT analysis revealed a significant reduction in bone volume/total volume, trabecular number and trabecular thickness, as well as significant increase in bone surface/volume ratio in tibiae with osteolytic lesions, suggesting active bone remodeling and bone loss. None of the changes in bone compositional properties were correlated with lesion area from radiographs or the changes in bone architecture from microCT. This study indicates that LNCaP C4-2B prostate cancer metastases alter bone tissue composition independent of changes in architecture, and altered bone quality may be an important contributor to fracture risk in these patients. Raman spectroscopy may provide a new avenue of investigation into interactions between tumor and bone microenvironment.

Imaging Breast Cancer Bone Metastases: Current Status and Future Directions

The skeleton is commonly affected in the context of metastatic breast cancer and is a cause of significant morbidity in these individuals. Therapeutic options include systemic therapy, radiotherapy, and surgery given with the intent of preserving function and quality of life. As the spectrum of available therapies increases, key challenges comprise reliable diagnosis of bony metastatic disease and accurate evaluation of response that permits rapid therapeutic transition in those responding inadequately prior to development of significant skeletal morbidity. The (99m)Tc-diphosphonate bone scan remains one of the most commonly requested investigations for skeletal evaluation in patients with breast cancer. However a time lag of 3-6 months for accurate response evaluation from the start of treatment limits its utility for response evaluation in routine clinical practice or as a progression end point in the research setting. Functional imaging strategies using more tumor-specific radiopharmaceuticals show promise as an effective means of imaging response at a clinically relevant time point and are the subject of this review.